By Hendra Lukman 
A pioneering gene therapy developed by scientists at University College London (UCL) and Great Ormond Street Hospital (GOSH) is showing remarkable promise for pediatric and adult patients battling T-cell acute lymphoblastic leukemia (T-ALL), a rare and aggressive form of blood cancer. This innovative approach, known as BE-CAR7, leverages genome-edited immune cells to precisely target and eradicate the disease, offering a lifeline to individuals with limited conventional treatment options. The therapy represents a significant advancement in the field of precision medicine, particularly for T-ALL, which has historically presented formidable challenges in treatment.
The Dawn of Base-Editing in Cancer Therapy
BE-CAR7 stands as a first-of-its-kind gene therapy that utilizes base-edited immune cells. Base-editing is an advanced and highly precise form of CRISPR gene-editing technology that allows for the modification of individual DNA letters within living cells without making double-strand breaks in the DNA. This precision minimizes the risk of unintended genetic alterations and chromosomal damage, a crucial safety consideration in therapeutic applications.
The genesis of this groundbreaking treatment can be traced back to 2022, when researchers at GOSH and UCL first employed this revolutionary base-editing technology to treat Alyssa, a 13-year-old girl from Leicester. Her case marked a historic moment, as it was the very first time a base-edited therapy had been administered to a patient globally. Since Alyssa’s pioneering treatment, the therapy has been extended to an additional eight children and two adults at GOSH and King’s College Hospital (KCH), demonstrating a growing commitment to expanding its reach and understanding its efficacy across a broader patient cohort.
Promising Clinical Trial Results Emerge
Early findings from the clinical trial investigating BE-CAR7 have been published in the prestigious New England Journal of Medicine and presented at the 67th American Society of Hematology Annual Meeting. These publications have illuminated the significant impact of this novel therapy, with researchers reporting strong remission rates. While specific quantitative data on remission rates for the entire cohort are still emerging from ongoing analyses, the initial results have been sufficiently compelling to warrant continued investigation and expansion of the trial. The early success in achieving disease clearance in patients who had exhausted standard treatment pathways underscores the transformative potential of BE-CAR7.
Understanding CAR T-cell Immunotherapy
To appreciate the significance of BE-CAR7, it is essential to understand the broader context of CAR T-cell therapy. Chimeric Antigen Receptor (CAR) T-cell immunotherapy has emerged as a powerful weapon against various blood cancers. The fundamental principle involves genetically modifying a patient’s own T-cells, a type of white blood cell crucial to the immune system. These T-cells are engineered to express a chimeric antigen receptor (CAR) on their surface. This customized receptor acts like a highly specific "homing device," enabling the modified T-cells to recognize unique markers, or "flags," present on the surface of cancer cells. Upon identification, the engineered T-cells are then activated to seek out and destroy these malignant cells.
However, developing CAR T-cell therapies for leukemias that originate from T-cells themselves has presented unique and considerable challenges. The primary hurdle lies in the delicate balance required: the treatment must effectively eliminate cancerous T-cells without inadvertently triggering the engineered cells to attack the body’s healthy T-cells, a phenomenon that could lead to severe autoimmune reactions or other life-threatening complications. This inherent complexity has historically limited the success of CAR T-cell approaches for T-ALL.
Base-Editing: The Key to Universal CAR T-cells
The breakthrough offered by BE-CAR7 lies in its ability to overcome these challenges through advanced base-editing. The BE-CAR7 T-cells are generated using a next-generation genome editing methodology that modifies single DNA letters without cleaving the DNA strand. This "cut-free" approach significantly reduces the risk of chromosomal damage, a critical safety enhancement. By precisely altering specific DNA sequences, researchers have been able to reprogram these T-cells.
A pivotal development in 2022 was the creation of banked stores of "universal" CAR T-cells using these base-editing techniques. These universal CAR T-cells are designed to be effective in a wide range of patients, regardless of their genetic makeup, and can be readily administered "off-the-shelf." This eliminates the lengthy and complex process of manufacturing personalized CAR T-cells for each individual, drastically improving treatment accessibility and turnaround time. For the BE-CAR7 study, these universal CAR T-cells were derived from the white blood cells of healthy donors. The intricate engineering process took place within a state-of-the-art clean room facility at GOSH, utilizing custom RNA, mRNA, and a lentiviral vector within an automated system meticulously refined by the research team.
The Therapeutic Journey: From Clearance to Immune Restoration
Once administered to patients, the base-edited BE-CAR7 T-cells embark on a targeted mission. They swiftly locate and eliminate T-cells throughout the body, with a particular focus on eradicating the leukemia-causing cells. In cases where the leukemia is successfully cleared within the first month of treatment, patients then proceed to a bone marrow transplant. This crucial step aims to restore a healthy and functional immune system, which is often compromised by the leukemia itself and the intensive treatment. The recovery and rebuilding of the immune system typically unfolds over the subsequent months.
Professor Waseem Qasim, the driving force behind this research and a Professor of Cell and Gene Therapy at UCL and Honorary Consultant Immunologist at GOSH, highlighted the significance of these findings. "We previously demonstrated promising results using precision genome editing for children with aggressive blood cancer, and this larger cohort of patients confirms the profound impact of this treatment modality," he stated. "We have successfully shown that universal or ‘off-the-shelf’ base-edited CAR T-cells can effectively seek and destroy highly resistant cases of CD7+ leukemia."
Professor Qasim also acknowledged the intensive nature of these therapies and the emotional toll on patients and families. "Numerous teams across the hospital and university were involved, and everyone is immensely gratified for the patients who have achieved disease clearance. However, we remain deeply aware that the outcomes were not as hoped for some children. These are demanding and challenging treatments, and patients and their families have been incredibly generous in recognizing the importance of learning as much as possible from each experience."
A Beacon of Hope for Treatment-Resistant Cases
Dr. Rob Chiesa, a key investigator in the study and a Bone Marrow Transplant Consultant at GOSH, emphasized the critical need for alternative therapies for a subset of T-ALL patients. "While the majority of children with T-cell leukemia respond well to standard treatments, approximately 20% may not. It is precisely these patients who desperately require improved options, and this research offers a significant beacon of hope for a better prognosis for all individuals diagnosed with this rare yet aggressive form of blood cancer."
Dr. Chiesa further lauded the resilience of patients like Alyssa. "Witnessing Alyssa’s continued progress is nothing short of extraordinary and a testament to her tenacity and the unwavering dedication of a vast army of individuals at GOSH. The seamless collaboration between bone marrow transplant specialists, hematologists, ward staff, educators, play therapists, physiotherapists, and laboratory and research teams, among many others, is absolutely vital in providing comprehensive support for our patients."
Echoing this sentiment, Dr. Deborah Yallop, a Consultant Hematologist at KCH, remarked, "We have observed highly impressive responses in clearing leukemia that previously appeared incurable – it is an exceptionally powerful approach."
Expanding Access Through Dedicated Funding
The ongoing clinical trial is sponsored by GOSH and benefits from crucial support from the Medical Research Council, Wellcome, and the National Institute for Health and Care Research (NIHR). Patients eligible for NHS care who are interested in participating in the trial are encouraged to consult with their healthcare providers.
In a significant stride towards broader accessibility, the GOSH Charity has committed substantial funding to support the treatment of an additional 10 T-ALL patients. This investment, exceeding £2 million, will not only broaden access to the trial but also bolster GOSH Charity’s ambitious fundraising campaign for a new Children’s Cancer Centre. This center is envisioned to be a hub for cutting-edge research and to accelerate the development and implementation of innovative cancer therapies.
Alyssa’s Journey: An Enduring Inspiration
Alyssa Tapley, now 16 years old, continues to be an inspiring figure. Her courageous decision to be the first person globally to receive a base-edited cell therapy has paved the way for countless others. In 2022, when her leukemia was undetectable, she remained under close medical surveillance. She has since transitioned to long-term follow-up and is fully immersed in daily life, enjoying activities with her friends.
Alyssa was diagnosed with T-cell leukemia in May 2021, following months of symptoms that initially mimicked recurrent viral illnesses and profound fatigue. Standard treatments, including chemotherapy and a bone marrow transplant, proved ineffective, and discussions about palliative care were underway when the research team offered her the experimental therapy.
Reflecting on her experience, Alyssa shared, "I chose to participate in the research because I felt that even if it didn’t work for me, it could help others. Years later, we know it worked, and I am doing incredibly well. I’ve been able to do all the things you’re supposed to do as a teenager. I’ve gone sailing, spent time away from home pursuing my Duke of Edinburgh Award, and even just attending school is something I once dreamed of when I was ill. I don’t take anything for granted. My next goal is to learn to drive, but my ultimate aspiration is to become a research scientist and be part of the next significant discovery that can help people like me."
A Foundation of Research Infrastructure and Collaboration
The development and manufacturing of BE-CAR7 cells are the culmination of a long-term research program conducted at the UCL Great Ormond Street Institute of Child Health, under the leadership of Professor Qasim. His ongoing dedication and expertise, coupled with his role as an honorary consultant at GOSH, have been instrumental. The project has been bolstered by crucial support from the NIHR, Wellcome, the Medical Research Council, and the GOSH Charity, all of which have played a pivotal role in driving the development of innovative genome-editing treatments.
The research team now operates from the state-of-the-art Zayed Centre for Research into Rare Disease in Children. This pioneering facility is a testament to the collaborative spirit between UCL and GOSH, made possible by a generous £60 million gift in 2014 from Her Highness Sheikha Fatima bint Mubarak, in honor of her late husband, Sheikh Zayed bin Sultan Al Nahyan.
The researchers extended their profound gratitude to Anthony Nolan, an organization dedicated to bone marrow donation, and to the selfless volunteer blood and stem cell donors. Their contributions, alongside the unwavering commitment of the patients and their families who chose to participate in this groundbreaking work, have been indispensable. The ongoing success of BE-CAR7 signifies a remarkable achievement in the fight against T-ALL, offering tangible hope and a path forward for those most affected by this challenging disease.
